Drug preparations for treating impotency

ABSTRACT

Topical gelled compositions comprising a drug for treating impotency dispersed within a polymer matrix and treatments using the complex.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/536,750 filed Sep. 29, 1995, abandoned, and a continuationin part of U.S. patent application Ser. No. 08/796,578 filed Feb. 6,1997, the entire contents of both applications being incorporated hereinby reference in their entirety.

FIELD OF THE INVENTION

This invention relates to the preparation of a transdermal deliverysystem. The preparation is designed to deliver therapeutic levels of adrug for treating impotency to specific sites below the dermal level ofthe skin.

DESCRIPTION OF THE PRIOR ART

Over the years, methods have been developed to achieve the efficientdelivery of a therapeutic drug to a mammalian body part requiringpharmaceutical treatment. Use of an aqueous liquid which can be appliedat room temperature as a liquid but which forms a semi-solid gel whenwarmed to body temperature has been utilized as a vehicle for some drugdelivery since such a system combines ease of application with greaterretention at the site requiring treatment than would be the case if theaqueous composition were not converted to a gel as it is warmed tomammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC®polyols are used in aqueous compositions to provide thermally gellingaqueous systems. Adjusting the concentration of the polymer provides thedesired sol-gel transition temperature, that is, the lower theconcentration of polymer, the higher the sol-gel transition temperature,after crossing a critical concentration minimum, below which a gel willnot form

In U.S. Pat. Nos. 4,474,751 and 4,478,822 drug delivery systems aredescribed which utilize thermosetting gels; the unique feature of thesesystems is that both the gel transition temperature and/or the rigidityof the gel can be modified by adjusting the pH and/or the ionicstrength, as well as by the concentration of the polymer.

Other patents disclosing pharmaceutical compositions which rely upon anaqueous gel composition as a vehicle for the application of the drug areU.S. Pat. Nos 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780.Thermosetting gel systems are also disclosed for application to injuredmammalian tissues of the thoracic or peritoneal cavities in U.S. Pat.No. 4,911,926.

Ionic polysaccharides have been used in the application of drugs bycontrolled release. Such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences, Volume78, Number 11, November 1989, Bodmeier et al. Calcium alginate gelformulations have also found use as a matrix material for the controlledrelease of herbicides, as disclosed in the Journal of ControlledRelease, (1986), pages 229-233, Pfister et al.

In U.S. Pat. No. 3,640,741, a molded plastic mass composed of thereaction product of a hydrophilic colloid and a cross-linking agent suchas a liquid polyol, also containing an organic liquid medium such asglycerin, is disclosed as useful in the controlled release of medicationor other additives. The hydrophilic colloid can be carboxymethylcellulose gum or a natural alginate gum which is cross-linked with apolyol. The cross-linking reaction is accelerated in the presence ofaluminum and calcium salts.

In U.S. Pat. No. 4,895,724, compositions are disclosed for thecontrolled release of pharmacological macromolecular compounds containedin a matrix of chitosan. Chitosan can be cross-linked utilizingaldehydes, epichlorohydrin and benzoquinone.

In U.S. Pat. No. 4,795,642, there are disclosed gelatin-encapsulated,controlled-release compositions for release of pharmaceuticalcompositions, wherein the gelatin encloses a solid matrix formed by thecation-assisted gellation of a liquid filling composition incorporatinga vegetable gum together with a pharmaceutically-active compound. Thevegetable gums are disclosed as polysaccharide gums such as alginateswhich can be gelled utilizing a cationic gelling agent such as analkaline earth metal cation.

While the prior art is silent with respect to aqueous drug deliveryvehicles and isotonicity thereof, osmotic drug delivery systems aredisclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chambercompartment for holding osmotic agents, adjuvants, enzymes, drugs,pro-drugs, pesticides, and the like. These materials are-enclosed bysemipermeable membranes so as to allow the fluids within the chambers todiffuse into the environment into which the osmotic drug delivery systemis in contact. The drug delivery device can be sized for oral ingestion,implantation, rectal, vaginal, or ocular insertion for delivery of adrug or other beneficial substance. Since this drug delivery devicerelies on the permeability of the semipermeable membranes to control therate of delivery of the drug, the drugs or other pharmaceuticalpreparations by definition, are not isotonic with mammalian blood.

Pharmacological erection therapy is an effective method to treat maleerectile dysfunction. The medications most commonly used have beenpapaverine hydrochloride, a smooth muscle relaxant, and phentolaminemesylate, an α-adrenergic blocker. Recent data have suggested thatprostaglandin E1 either alone or in combination with papaverine producesan improved erectile response. To date, however, there have been littleobjective data comparing the relative efficacy of these medicationseither alone or in combination. Furthermore, the use of these drugs hasrequired special applicators, which besides being cumbersome, are alsopainful to use.

A need thus exists for the administration of active therapeutic agentsthat can be applied topically and transported through the skin oradministered by injection without the concommittant presence of pain.

SUMMARY OF THE INVENTION

The present invention relates to the formation of a gelled compositionand its use in treating impotency, or erectile dysfunction. Moreparticularly, this invention relates to a composition containing atherapeutic drug for treating impotency, which comprises: a polymermatrix composed of a highly negative charged polymer material which maybe selected from the group consisting of polysulfated glucosoglycans,glycosaminoglycans, mucopolysaccharides and mixtures thereof, and anonionic polymer which may be selected from the group consisting ofcarboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose, and mixtures thereof.

Another embodiment of this invention involves a method for the treatmentof impotency in male animals, which comprises applying either topicallyor by injection into the corpus cavernosa therapeutically effectivedoses of a gelled suspension of a composition comprising ananti-impotency drug dispersed within a polymer matrix which is suspendedin a liquid medium. Preferably, one of the polymer materials has a meanaverage molecular weight below about 800,000, and the other polymer is anonionic cellulose derivative. The present invention utilizes a novelcombination of polymers each having a specific ionicity. Morespecifically, the polymers used in the formulation are of two basictypes: those which have a strong negative charge, and those which arenon-ionic or have no charge attached to them.

DETAILED DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that an effective therapeutic levelof a drug may be administered topically and transdermally deliveredthrough the skin into various sites where the drug is therapeuticallyeffective. In order for this to be accomplished, it has been discoveredthat the active drug must be suspended or entrapped in a speciallydesigned polymer matrix containing a specific molar ratio of negativelycharged polymers and a non-ionic polymer suspended or dissolved in waterand solubilizers.

This system is believed to form a matrix which microencapsulates,suspends, and/or entraps the active drug entity such that when it isadministered, it is slowly released into the systemic circulatory systemor muscular tissue providing a method of delivering an active drug to anaffected site in the body through the skin.

The molar ratio of the polymers present in the matrix is critical inthis invention. It has been found that molar ratios of the negativelycharged polymer to the non-ionic polymer must be from 1:0.5 to 4, andpreferably from 1:0.5 to 2.0, and most preferably from 1:0.7 to 2.5. Fortransdermal delivery of drugs, it has been found that ratios eitherhigher or lower than these levels will result in a polymer shearingeffect which produces unacceptable turbulence and air pockets in thecomposition with resulting loss of potency and efficacy. Furthermore,the solutions tend to separate and form distinct polymer layers whenionic molarity is not appropriate.

At least one of the polymers used to form the matrix of this inventionmust be sufficiently negatively charged to aid in the dispersion,encapsulation or solubilization of the drug. Particularly preferredpolymers which have mean average molecular weights below about 800,000and preferably molecular weights between 650,000 to 800,000 have beenfound acceptable to form usable polymer matrixes for transdermaldelivery. Polymers with mean average molecular weights between 700,000and 775,000 are most preferred. Polymers having molecular weights aboveabout 800,000 form solid gels in solution and are unable to serve aspart of a transdermal delivery system. Furthermore, the polymers must besterilizable and be stable during sterilization so that the polymer doesnot lose molecular weight once formulated into the final transdermaldelivery form.

Exemplary, non-limiting examples of compounds that may be used as asource of this molecular weight polymer include polysulfatedglucosoglycans, glycosaminoglycans, and mucopolysaccharides, derivativesthereof and mixtures thereof. Particularly preferred mucopolysaccharidesare chondroitin sulfate and hyaluronic acid salts. Exemplary hyaluronatesalts include sodium, calcium, potassium and magnesium salts withhyaluronate sodium being most preferred.

Hyaluronic acid (HA) occurs naturally in joint synovial fluid, where itplays a lubricating role, and may have biological activity was well. HAis a mucopolysaccharide, and may alternatively be referred to asglycosamfnoglycan. The repeating unit of the hyaluronic acid molecule isa disaccharide consisting of D-glucuronic acid andN-acetyl-D-glucosamine. Because hyaluronic acid possesses a negativecharge at neutral pH, it is soluble in water, where it forms highlyviscous solutions. The D-glucuronic acid unit and N-acetyl-D-glucosamineunit are bonded through a glycosidic, beta (1-3) linkage, while eachdisaccharide unit is bonded to the next disaccharide unit through a beta(1-5) linkage. The (beta 1-4) linkages may be broken through hydrolysiswith the enzyme hyaluronidase.

A variety of substances, commonly referred to as hyaluronic acid, havebeen isolated by numerous methods from various tissue sources includingumbilical cords, skin, vitreous humour, synovial fluid, tumors,haemolytic streptocci pigskin, rooster combs, and the walls of veins andarteries. It is also being synthesized artificially and by recombinanttechnology.

Conventional methods for obtaining hyaluronic acid results with aproduct having differing properties and a wide range of viscosities.U.S. Pat. No. 2,585,546 to Hadian, discloses an example of a method forobtaining hyaluronic acid and which involves extracting acetone-washedumbilical cords with a dilute salt solution, acidifying the resultingextract, removing the clot so formed, precipitating some hyaluronic acidwith protein from the acidified extract with ammonium sulfate, agitatingthe liquid with pyridine, precipitating another fraction highlycontaminated with protein, followed by more ammonium sulfate whichforces some pyridine out of solution along with the high viscosityhyaluronic acid. The hyaluronic acid collects at the interface betweenthe two liquid phases and may be separated by filtration, centrifugationor another usual procedure. A modification of this process involves thefractionation of the acidic salt extract from umbilical cords withalcohol and ammonium sulfate. Alcohol is added to the acidic saltextract, and the resulting precipitate is removed. Solid ammoniumsulfate is added to the liquid until saturation and the solution formstwo phases with a precipitate of hyaluronic acid at the interface.

U.S. Pat. No. 4,517,296 to Bracke et al. is directed to the preparationof hyaluronic acid in high yield from Streptococcus bacteria byfermenting the bacteria under anaerobic conditions in a CO₂ enrichedgrowth medium, separating the bacteria from the resulting broth andisolating the hyaluronic acid from the remaining constituents of thebroth. Separation of the microorganisms from the hyaluronic acid isfacilitated by killing the bacteria with trichloroacetic acid. Afterremoval of the bacteria cells and concentration of the higher molecularweight fermentation products, the hyaluronic acid is isolated andpurified by precipitation, resuspension and reprecipitation.

One particular fraction of hyaluronic acid (HA) that exhibits excellentmatrix formation according to the present invention is hyaluronatesodium having a mean or average molecular weight between650,000-800,000, preferably 700,000-775,000 with a high degree ofpurity, 95-100% free, and preferably at least 98% pure, fromcontamination of related mucopolysaccharides. Furthermore, thishyaluronic acid has a sulphated ash content of less than 15% and aprotein content of less than 5%. Examples of usable base salts includethose safe from animal and human use, such as sodium, potassium,calcium, and magnesium salts or the like.

In contrast to HA, chondroitins are mucopolysaccharides comprisingrepeating units of D-glucuronic acid and N-acetyl-D-galactosamine.Chondroitin sulphates are important components of cartilage and bone andare excellent for preparing the polymer matrix herein.

The negative charged polymers are generally present in the system inamounts which enable a solid gel to be formed. Generally, gels areformed using amounts of about 2.0 to about 3.0% by weight with amountsof about 2.1 to about 2.5% by weight being preferred for use as atopical gel.

The solutions used to prepare the gels of the present invention may beprepared in a variety of ways. For example, the polymers may bedissolved in water and purified either separately or jointly and thenthe optional active drug added to the system.

A particularly preferred procedure involves separately dissolving thenonionic polymer in water and centrifuging the material to form asolution and remove impurities. This may be conveniently done atrotation speeds of 2000 rpm for times of about 30 minutes to about twohours.

In contrast, the negative charged polymer may be blended and stirred inwater until it is dissolved. This process must be done while avoidingthe formation of bubbles and while freeing the polymer of itselectrostatic activity. Furthermore, the molecular weight of the polymermust not be significantly changed during processing and as such mildprocess conditions are required. Processing conditions of 400-3000 rpmfor durations of 16-24 hours have been found acceptable to producestable solutions or gels of the charged polymer.

Conventional pharmaceutically acceptable emulsifiers, suspending agents,antioxidants (such as sodium meta-bisulfate) and preservatives (such asbenzyl alcohol) may then be added to this system. Once all thecomponents are blended together, such as by mixing 400-3000 rpm for oneto four hours, the system is filled into tubes and sterilized. Theresulting system is a clear gel which is storage stable for severalyears.

The drug may be added to the homogenous solution or gel separately oncedissolved or disbursed in water. Emulsifiers, suspending agents andpreservatives may then be added to this system. One particularlynonlimiting effective material for solubilizing water insoluble drugs ismethoxypolyethylene glycol (MPEG) Once all the components are blendedtogether, for 400-3000 rpm for 1 to 4 hours, the system is filled intotubes and sterilized. The resulting system is storage stable for severalyears.

The formulations may be used topically and also contain conventionalpharmaceutically acceptable excipients well known to those skilled inthe art, such as surfactants, suspending agents, emulsifiers osmoticenhancers, extenders and dilutants, pH modifiers as well as fragrances,colors, flavors and other additives.

As indicated above, the active drug agents may be blended with theaqueous polymer matrix at the time of manufacture. As such, the drugwhen in the form of a water-soluble solid is simply diluted withsterilized water or polymer matrix solution and prepared in gel form.

The dosage system can be formed with or without the use ofpharmaceutically acceptable preservatives. A significant advantage ofthe dosage form of the present system relates to its ability to allowthe drug to slowly diffuse through tissue when administered thusallowing for an effective therapeutic dose to be present for longperiods of time, i.e., 15 minutes to several hours.

In this regard, it should be noted that reference to therapeuticallyeffective dose does not necessarily relate to conventional dosagelevels, but does relate to drug levels that achieve an effectivetherapeutic level at the dose employed, which may be the same level butnot at the same frequency of administration previously required fordrugs taken orally or by injection. This not only significantly reducesthe number of doses required to achieve the same effect, but it alsoreduces costs, maintenance and health hazards associated withconventional treatment therapies.

Doses may vary from patient to patient depending on the type andseverity of the condition being treated and the drug being administered.Generally, doses of 150 mcg to 1000 mcg may be administered withpreferred doses using 200 to 500 mcg of drug disbursed in the gelledmatrix system. The total dosage of the gelled matrix with drug isusually 0.5 ml to 5 ml in volume.

It is generally recognized that primary erectile dysfunction is almostalways due to intrapsychic factors. In rare cases, biogenic factors,usually associated with low testosterone levels and reflecting disordersof the hypothalamic-pituitary-gonadal axis, provide the major etiology.Occasionally, vascular abnormalities are found. Physical factors includesystemic diseases (e.g., diabetes mellitus the most common!, syphilis,alcoholism, drug dependency, hypopituitarism, and hypothyroidism); localdisorders (e.g., congenital abnormalities na inflammatory diseases ofthe genitalia); vascular disturbances such as aortic aneurysm andatherosclerosis (edg., Leriche's syndrome); neurogenic disorders (e.g.,multiple sclerosis, spinal cord lesions, pituitary mifcroadenoma withhyperprolactinemia, and cardiovascular accident); drugs such ashypertensives, sedatives, tranquilizers, and amphetamines; and surgicalprocedures such as sympathectomy, prostatectomy and castration producevarying effects. Impotence is usually not induced by transurethralprostatectomy, whereas it almost always occurs after perinealprostatectomy. However, retrograde ejaculation is produced in the vastmajority of men, irrespective of the type of prostatectomy.

Pharmacological erection therapy is an effective method to treat maleerectile dysfunction. The medications most commonly used have beenpapaverine hydrochloride, a smooth muscle relaxant, and phentolaminemesylate, an α-adrenergic blocker. Recent data have suggested thatprostaglandin E1 either alone or in combination with papaverine producesan improved erectile response.

There currently is increasing evidence that prostaglandin E1 ispresently the single most effective agent for pharmacological erectiontherapy. Prostaglandin E1 is a physiological agent that is metabolizedlocally within the cavernous tissue and there appears to be a lowincidence of corporeal fibrosis, priapism or systemic reactionsassociated with its use. Several studies using subjective evaluationhave shown that prostaglandin E1 is more effective than a combination ofpapaverine and phentolamine. Lee et al found that two-thirds of the menwho failed prior intracavernous therapy with papaverine and phentolamineachieved adequate erections with prostaglandin E1. Prostaglandin E1 hasalso been found to be extremely effective as a single agent in severalother studies. Liu et al recently reported that prostaglandin E1 is atleast as effective as papaverine in increasing penile blood flowmeasured by duplex sonography. Prostaglandin E1 has the advantage overpapaverine of a slower onset, longer maintenance and less chance ofpriapism.

Despite these advantages, however, prostaglandin E1 is associated with asignificant incidence of penile discomfort.

Prostaglandin E1 is a naturally occurring acidic lipid that issynthesized from fatty acid precursors by most mammalian tissues and hasa variety of pharmacologic effects. Human seminal fluid is a rich sourceof prostaglandins, including PGE₁ and PGE₂, and the total concentrationof prostaglandins in ejaculate has been estimated to be approximately100-200 mcg/mL. In vitro, alprostadil (PGE₁) has been shown to causedose-dependent smooth muscle relaxation in isolated corpus cavernosumand corpus spongiosum preparations. Additionally, vasodilation has beendemonstrated in isolated cavernosal artery segments that werepre-contracted with either norepinephrine or prostaglandin E₂α. Thevasodilatory effects of alprostadil on the cavernosal arteries and thetrabecular smooth muscle of the corpora cavernosa result in rapidarterial inflow and expansion of the lacunar spaces within the corpora.As the expanded corporal sinusoids are compressed against the tunicaalbuginea, venous outflow through subtunical vessels is impeded andpenile rigidity develops. This process is referred to as the corporalveno-occlusive mechanism.

The most notable systemic effects of alprostadil are vasodilation,inhibition of platelet aggregation, and stimulation of intestinal anduterine smooth muscle. Intravenous doses of 1 to 10 micrograms perkilogram of body weight lower blood pressure in mammals by decreasingperipheral resistance. Reflex increases in cardiac output and heart ratemay accompany these effects.

Alprostadil is rapidly metabolized locally by enzymatic oxidation of the15-hydroxyl group to 15-keto-PGE₁. The enzyme catalyzing this processhas been isolated from many tissues in the lower genitourinary tractincluding the urethra, prostate, and corpus cavernosum. 15-keto-PGE₁retains little (1-2%) of the biological activity of PGE₁. 15-keto-PGE₁is rapidly reduced at the C₁₃ -C₁₄ position to form the most abundantmetabolite in plasma, 13,14-dihydro,15-keto PGE₁ (DKH-PGE₁), which isbiologically inactive. The majority of DKH-PGE₁ is further metabolizedto smaller prostaglandin remnants that are cleared primarily by thekidney and liver. Between 60% and 90% of PGE₁ has bene shown to bemetabolized after one pass through the pulmonary capillary beds.

Use of the present formulations either alone or in combination withvarious therapeutic agents overcomes all of these prior artdeficiencies.

Regardless of the route of administration elected, the formulations ofthe present invention are formulated into pharmaceutically acceptabledosage forms by conventional methods known in the pharmaceutical art.

As discussed above, an effective but nontoxic amount of the system isemployed in treatment. The dose regimen for administering drugs ortreating various conditions, such as pain as described above, isselected in accordance with a variety of factors including the type,age, weight, sex, and medical condition of the subject, the severity ofthe pain, the route of administration and the particular complex orcombination of drugs employed. Determination of the proper dose for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum doses of the compound. Thereafter, the dose is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired. Generally, amountsof drug may vary from 0.0001% to about 75% by weight of the system whenusing topically with 0.5 to 5 ml concentrations and preferably in 1 to 3ml amounts.

The formulations of this invention are particularly useful in theadministration of drugs that could be previously administered only byinjection.

The transdermal delivery system described herein offers a majoralternative especially for those individuals who have a history ofundesirable side-effects associated with irritation and/or pain from theinjection. Also for those patients who have already suffered damage, thetransdermal preparations described herein present a new way of providingeffective treatment and relief of painful symptoms.

In addition to the negatively charged polymers, the transdermal polymermatrix must contain a non-ionic polymer which facilitates in retardingthe absorption of the active drug through the skin and delays or slowsdown in animals natural absorption of the negatively charged polymer.

Without the presence of this component, the active drug would not bedelivered transdermally into the site targeted for treatment at levelswhich are therapeutically effective. In addition to the non-ionicpolymers described in this system, these materials are necessary toprovide thorough penetration of skin layers including the epidermis,dermis and fatty tissue layers.

Particularly preferred nonionic polymers are cellulose derivatives andparticularly those selected from the group consisting ofcarboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose and mixtures thereof. These particular polymers have beenfound to possess exceptional ability to form sustained release matrixformulations when used in combination with a negatively charged polymer.Such polymers are generally employed in amounts of about 0.1% to about1.5% and preferably about 0.5 to about 1.4%. Amounts above about 1.5%result in the formation of a solid gel when used with the negativelycharged polymer. Amounts below about 0.1% have not been found suitableto prepare a storage stable product that has sustained drug release.

A particularly preferred HEC concentration is about 0.2% to about 1.0%by weight of the matrix.

A wide variety of medicaments which may be administered topically may beused in the delivery system according to this invention. These includedrugs, without limitation, papaverine hydrochloride, phentolaminemesylate and prostaglandin E1, and mixtures thereof.

One particular criteria of the drug is that they must be solubilized inthe polymer matrix solution in order to be topically administered.

The following examples are illustrative of preferred embodiments of theinvention and are not to be construed as limiting the invention thereto.All polymer molecular weights are mean average molecular weights. Allpercentages are based on the percent by weight of the final deliverysystem or formulation prepared unless otherwise indicated and all totalsequal 100% by weight.

EXAMPLE 1

This example demonstrates the formation of a transdermal preparation ofalprostadil.

The dosage range for the drug is between 2-3 ml.

    ______________________________________    Aprostadil               250 mcg    Sodium hyaluronate (HA)  2.5%    Hydroxyethyl cellulose (HEC)                             0.7%    Methoxypolyethylene glycol (MPEG)                             10%    Benzyl alcohol           1%    Water                    Remainder    ______________________________________

BATCH SIZE 1000 ml

1. Into a sterilized glass vessel is added 1062.5 ml of sterile waterwhich is stirred at 1500 to 2000 rpm. Slowly add 34.5 grams of HA,having a molecular weight of around 700,000 to 775,000 and a puritydescribed above. Allow to stir for 16 to 20 hours until all of the HApolymer has dissolved into the water and a crystal-clear viscoussolution has formed.

2. Prepare a 0.7% solution of HEC by adding 10.5 grams of the solidmaterial under aseptic conditions to 250 ml of sterile water. Allow todissolve for 1 to 2 hours while stirring at 1500 to 2000 rpm. Add theHEC solution to a sufficient amount of the HA solution and mix for 10 to15 hours until a homogeneous solution is produced.

3. Carefully measure 100 ml of methoxypolyethylene glycol (MPEG) 10%into the mixture. RPM speeds should be increased for the mixture whilethis step is being performed to 2500 rpm. The resulting mixture thusformed should be allowed to mix at 2000 rpm for an additional 3 to 4hours.

4. At this point 1% of benzol alcohol or 10 ml is added to the mixture.Again, the rpm speed is increased during this part of the procedure to2500. The mixture should be allowed to mix for 3 to 5 hours at 2000 rpm.

5. Using safe techniques, 250 mg of aprostadil should be slowly added tothe mixture. Again the rpm speed for the purpose of addition of drugshould be increased to 2500, and the entire drug should be completedwithin 15 minutes.

The final mixture is clear with a slight tint following 15 to 20 hoursof further mixing at 2000 rpm. The final product should be transferred,using aseptic technics, to 1-5 ml tubes.

When used, approximately 2 ml of matrix is applied to the exteriorsurface of the penis 10 to 15 minutes before intercourse. Alternatively,approximately 2 ml may be infused into the urethra 10 to 15 minutesbefore intercourse. Either technique results in the formation of anerection.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A method for the treatment of erectiledysfunction in male animals, which comprises:topically applying to apenis a therapeutically effective amount of a drug for treatingimpotency dispersed within a gelled composition comprising a polymermatrix which is suspended in a liquid medium; wherein the polymer matrixcontains a negatively charged polymer blended with a nonionic polymerselected from the group consisting of hydroxyethyl cellulose,hydroxypropyl cellulose and mixtures thereof; and wherein the molarratio of the negative charged polymer to the nonionic polymer is 1:0.5to 4 and the negative charged polymer is present in amounts of about2.0% to about 3.5% by weight.
 2. The method of claim 1, wherein thenegatively charged polymer is selected from the group consisting ofglycosaminoglycans, mucopolysaccharides and mixtures thereof.
 3. Themethod of claim 1, wherein the negatively charged polymer is chondroitinsulfate or hyaluronate salt of sodium, calcium, potassium or magnesium.4. The method of claim 3, wherein the hyaluronate salt is the sodiumsalt and has a sulphonated ash content below about 15%, a proteincontent below about 5% and purity of at least 98%.
 5. The method ofclaim 1, wherein the therapeutically effective amount of drug in thegelled composition is selected from the group consisting of papaverine,phentolamine, prostaglandin E1, and mixtures thereof.
 6. The method ofclaim 1, wherein the therapeutically effective dose penetrates theexterior layers of the penis causing an erection without significantlymodifying motor or sensory functions.
 7. A gelled composition fortreating impotency, which comprises: a therapeutically effective amountof a drug for treating impotency dispersed within a matrix containing anegatively charged polymer which is sodium hyaluronate blended with anonionic polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropyl cellulose and mixtures thereof, wherein themolar ratio of the negative charged polymer to the nonionic polymer is1:0.5 to 4 and the negative charged polymer is present in amounts ofabout 2.0% to about 3.0% by weight.
 8. A method for the treatment oferectile dysfunction in male animals, which comprises:injecting into thecorpus cavernosa a therapeutically effective amount of a drug dispersedwithin a gelled composition comprising a polymer matrix which issuspended in a liquid medium; wherein the polymer matrix contains anegatively charged polymer blended with a nonionic polymer selected fromthe group consisting of hydroxyethyl cellulose, hydroxypropyl celluloseand mixtures thereof; and wherein the molar ratio of the negativecharged polymer to the nonionic polymer is 1:0.5 to 4 and the negativecharged polymer is present in amounts of about 2.0% to about 3.5% byweight.
 9. The method of claim 8, wherein the negatively charged polymermaterial is selected from the group consisting of glycosaminoglycans,mucopolysaccharides and mixtures thereof.
 10. The method of claim 8,wherein the negatively charged polymer material is chondroitin sulfateor hyaluronate salt of sodium, calcium, potassium or magnesium.
 11. Themethod of claim 10, wherein the hyaluronate salt is the sodium salt andhas a sulphated ash content below about 15%, a protein content belowabout 5% and purity of at least 98%.
 12. The method of claim 8, whereinthe therapeutically effective amount of drug in the gelled compositionis selected from the group consisting of papaverine, phentolamine,prostaglandin E1, and mixtures thereof.
 13. The method of claim 8,wherein the therapeutically effective dose penetrates the exteriorlayers of the penis causing an erection without significantly modifyingmotor or sensory functions.
 14. A method for the treatment of erectiledysfunction in male animals, which comprises:topically applying to apenis a therapeutically effective amount of a drug for treatingimpotency dispersed within a gelled composition comprising a polymermatrix which is suspended in a liquid medium; wherein the polymer matrixcontains a negatively charged polymer blended with a nonionic polymerselected from the group consisting of hydroxyethyl cellulose,hydroxypropyl cellulose and mixtures thereof; and wherein the molarratio of the negative charged polymer to the nonionic polymer is 1:0.5to 4 and the negative charged polymer is present in amounts of about2.0% to about 3.5% by weight; and wherein the drug for treatingimpotency is prostaglandin E₁.